Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-01 DOI:10.1172/JCI178628
Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen
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Abstract

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent anti-tumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.

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双重靶向巨噬细胞和小胶质细胞是PTEN缺陷胶质母细胞瘤模型的治疗漏洞。
肿瘤相关巨噬细胞和小胶质细胞(TAMs)对胶质母细胞瘤(GBM)(一种无法治愈的脑癌)的肿瘤进展和耐药性至关重要。我们以前曾发现溶酶体氧化酶(LOX)和橄榄酰肌肽样-3(OLFML3)分别是 GBM 中不可或缺的巨噬细胞和小胶质细胞趋化因子。本文通过单细胞转录组学和多重序列免疫荧光以及功能研究证明,巨噬细胞与小胶质细胞在 GBM 肿瘤微环境中呈负相关。在 PTEN 缺失的 GBM 细胞中抑制 LOX 可通过 NF-κB-PATZ1 信号通路上调 OLFML3 的表达,从而诱导小胶质细胞浸润的补偿性增加。通过抑制LOX和CLOCK-OLFML3轴来双重靶向巨噬细胞和小胶质细胞可产生强大的抗肿瘤效果,在PTEN缺陷的GBM小鼠模型中与抗PD1疗法联合使用时,60%以上的动物肿瘤可完全消退。因此,我们的研究结果为这种致命疾病提供了一种转化三联治疗策略。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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